Monoclonal antibody (mAb) treatment of organ transplant recipients has been a major development in the treatment of allograft rejection. The advantages of mAbs include their known specificity, consistent biological activity, and ease of administration. Of all mAbs clinically and experimentally tested in man, the most efficacious is the OKT3 mAb which recognizes the T cells receptor (TcR) complex on the surface of alloreactive cells. However, several limitations to the use of the OKT3 reagent persists. These include the significant adverse reactions following the initial dose, production by the recipient of antibodies to the OKT3 antibody, and the broad transient nature of the induced immunosuppression. Our laboratory has recently developed the first anti-murine CD3 mAb that reacts with all mouse T cells expressing a TcR complex. Initial studies in the laboratory suggest that treatment with the mAb in vivo has profound long term immunosuppressive effects including prolonged skin graft survival and depressed cellular immunity. It appears that the initial immunosuppression is a consequence of T cell depletion and receptor blockade. In addition, T cells that survive treatment may continue to be hyporesponsive. Thus, this hamster mAb provides the first anti- CD3 that can be used in a well-defined small animal model to provide a systematic evaluation of the use of anti-CD3 in vivo to suppress transplantation responses. Anti-CD3 antibodies not only function to suppress immune responses but can function as an antigen-non-specific mitogen capable of activating a variety of T cell functions. Thus, a major potential; of anti-CD3 treatment in vivo may lie in its ability to facilitate ongoing antigen-specific immune response, enhance bone marrow engraftment and augment immune potential of immunocompromised individuals. In this regard, preliminary findings suggest that in vivo treatment with low doses of anti-murine CD3 mAb results in a substantial activation of T cells including IL-2 receptor expression, secretion of lymphokines such as colony stimulating factor (CSF) and extramedullary hematopoiesis. Thus, these activating in vivo effects, previously not recognized in human studies, may provide a model system for analyzing the immunopotentiating effects of anti-CD3 mAb in vivo.